AB0077 IN RHEUMATOID ARTHRITIS PATIENTS, TOTAL IgA1 AND IgA2 LEVELS ARE ELEVATED: IMPLICATIONS FOR THE MUCOSAL ORIGIN HYPOTHESIS
Authors: V. Derksen, C. Allaart, A. van der Helm-van Mil, T. Huizinga, R. Toes, D. van der Woude
Journal: Annals of the Rheumatic Diseases (2022)

Background Mucosal surfaces may be involved in the pathophysiology of rheumatoid arthritis (RA) (1). IgA is the most abundant class of immunoglobulin at mucosal sites. Therefore, it is worthwhile to study this isotype in RA patients in more detail. Humans have two IgA subclasses, IgA1 and IgA2, which are not evenly distributed. IgA1 is dominant in serum, whereas IgA1 and IgA2 are more balanced at mucosal surfaces (2). Besides these differences in location, IgA2 has also been ascribed pro-inflammatory properties (3). Objectives As IgA subclasses might provide new insights into mucosal involvement and potential pro-inflammatory mechanisms, we investigated total and autoantibody-specific IgA subclasses responses in sera of rheumatoid arthritis patients. Methods Sera from two cohorts of RA patients, the IMPROVED (baseline visit) and the EAC (1-year visit), were selected based on previous autoantibody measurements. All patients fulfilled the 1987 (EAC) or 2010 (IMPROVED) ACR criteria for RA. Total IgA subclasses and IgA subclasses of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) were measured using (in-house) ELISA’s, and compared to healthy donors. Associations between these IgA subclass levels and markers of inflammation (CRP and disease activity score (DAS)) were investigated using Spearman’s rank correlation. Mann–Whitney U tests were performed to investigate the association between IgA1 and IgA2 levels and smoking, a proxy for chronic mucosal inflammation. To correct for confounders, a multivariate linear model including age, gender, CRP and smoking was used. Results Total IgA1 and IgA2 levels were increased in RA patients compared to healthy donors in both cohorts (Figure 1A-C, data IMPROVED). This increase was more pronounced in seropositive RA versus seronegative RA. Both total IgA subclasses were raised to the same extent, since the percentage of IgA2 of total IgA in serum did not differ between patients and healthy donors. In seropositive patients, RF and anti-CCP2 IgA1 and IgA2 could be detected, but measurements of anti-CCP2 IgA2 levels proved challenging due to interference of RF IgA. Although IgA2 has been postulated to be more proinflammatory, no correlations were found between total, RF and ACPA IgA subclass levels and DAS. An association between CRP and RF IgA2 was observed, but the effect size was small and did not remain significant after correction for multiple testing in the EAC. In smoking seropositive RA patients, a trend towards a selective increase in total IgA2 and RF IgA1 and IgA2 was observed (Figure 1D, data IMPROVED seropositive RA). Figure 1. Conclusion Seropositive RA patients have raised IgA1 and IgA2 levels and can also harbor RF and ACPA IgA subclasses. No shift towards IgA2 was observed, indicating that the increase in total IgA is not due to translocation of mucosal IgA into the bloodstream. However, chronic mucosal inflammation might be one of the mechanisms involved in the raise in IgA(2) levels in RA, given the association between smoking and total IgA2 levels. Despite its’ pro-inflammatory properties, no strong associations between IgA2 and markers of inflammation were found, which suggests that IgA2 does not play a essential role in the ongoing pro-inflammatory processes in RA patients. References [1]Holers VM, Demoruelle MK, Kuhn KA, et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nature Reviews Rheumatology. 2018;14(9):542-57. [2]Woof JM, Russell MW. Structure and function relationships in IgA. Mucosal Immunol. 2011;4(6):590-7. [3]Steffen U, Koeleman CA, Sokolova MV, et al. IgA subclasses have different effector functions associated with distinct glycosylation profiles. Nat Commun. 2020;11(1):120. Disclosure of Interests None declared